Genotype-directed Targeted Therapy for Pediatric Vascular Malformations: A Systematic Review

Pediatric vascular malformations are rare, heterogeneous disorders increasingly driven by somatic mutations affecting key molecular pathways, particularly the PI3K-AKT-mTOR and RAS-MAPK signaling cascades. Advances in genomic profiling have enabled the use of targeted pharmacological therapies, but the available evidence remains fragmented.

To systematically review the clinical outcomes and safety of genotype-directed targeted systemic therapies in pediatric patients with genetically characterized vascular malformations.

A systematic literature search was conducted in PubMed, Embase, and Scopus from database inception to November 21, 2025. Eligible studies included case reports, case series, cohort studies, and prospective investigations reporting genotype-directed targeted therapy in patients aged 0-18 years. Data on genetic alterations, targeted therapies, clinical and radiologic outcomes, and adverse events were extracted and synthesized qualitatively.

Fifty-two studies were included, reporting pediatric patients from the neonatal period to 18 years of age. The most frequently identified genetic alterations involved the PI3K-AKT-mTOR and RAS-MAPK pathways, predominantly PIK3CA and RAS-pathway mutations. Sirolimus, alpelisib, and trametinib were the most commonly used targeted agents. Many patients demonstrated clinical improvement and radiologic stabilization or lesion reduction following targeted therapy. Grade 3-4 adverse events were uncommon and generally manageable with dose modification or temporary treatment interruption.

Genotype-directed targeted therapies appear to provide clinical and radiologic benefit in pediatric vascular malformations with acceptable safety profiles. However, the current evidence is largely derived from observational studies and requires prospective validation through standardized investigations.